Dynamin-1-like protein is a GTPase that regulates mitochondrial fission. In humans, dynamin-1-like protein, which is typically referred to as dynamin-related protein 1 (Drp1), is encoded by the DNM1Lgene.[1][2][3]
Drp1, which is a member of the dynamin superfamily of proteins, consists of a GTPase and GTPase effector domain that are separated from each other by a helical segment of amino acids.[4] There are 3 mouse and 6 human isoforms of Drp1, including a brain-specific variant.[5] Drp1 exists as homooligomers and its function relies on its oligomerization ability.[6]
Function
Mitochondria routinely undergo fission and fusion events that maintain a dynamic reticular network. Drp1 is a fundamental component of mitochondrial fission.[7] Indeed, Drp1 deficient neurons have large, strongly interconnected mitochondria.,[8] due to dysfunctional fission machinery. Fission helps facilitate mitophagy, which is the breakdown and recycling of damaged mitochondria. Dysfunction in the DRP activity may result in mutated DNA or malfunctioning proteins diffusing throughout the mitochondrial system. In addition, fission results in fragmented mitochondria more capable of producing of reactive oxygen species, which can disrupt normal biochemical processes inside of cells.[9] ROS can be formed from incomplete transfer of electrons through the electron transport chain. Furthermore, fission influences calcium flux within the cell, linking Drp1 to apoptosis and cancer.[10]
Several studies have indicated that Drp1 is essential for proper embryonic development. Drp1 knockout mice exhibit abnormal brain development and die around embryonic day 12. In neural specific Drp1 knockout mice, brain size is reduced and apoptosis is increased. Synapse formation and neurite growth are also impaired. A second group of researchers generated another neural specific knockout mouse line. They found that knocking out Drp1 resulted in the appearance of large mitochondria in Purkinje cells and prevented neural tube formation.[5]
In humans, loss of Drp1 function affects brain development and is also associated with early mortality.[4]
Interactions
The majority of knowledge about mitochondrial fission comes from studies with yeast. The yeast homolog of Drp1 is dynamin-1 (Dnm1), which interacts with Fis1 through Mdv1. This interaction causes Dnm1 to oligomerize and form rings around dividing mitochondria at the so-called "constriction point".[4][11] Drp1 has also been shown to interact with GSK3B.[2] In mammals, Drp1 receptors include Mff, Mid49 and Mid51[12][13]
Drp1 has two major phosphorylation sites. The CDK phosphorylation site is S579, and the PKA site is S600 in Drp1 isoform 3. Phosphorylation by CDK is thought to be activating, whereas PKA phosphorylation is thought to be inhibitory. Recently, CaMKII was shown to phosphorylate Drp1 at S616. This was shown to occur in response to chronic Beta-adrenergic stimulation and to promote mPTP opening.[15] Other post-translational modifications include S-nitrosylation, sumoylation, and ubiquitination. Higher S- nitrosylation modifications of Drp1, which enhances Drp1 activity, have been observed in Alzheimer’s Disease. Furthermore, Drp1 has been shown to interact with Aβ monomers, thought to play an important role in Alzheimer’s Disease, exacerbating the disease and its symptoms.[16] Drp1 has been linked to a number of pathways and processes including cell division, apoptosis, and necrosis. Drp1 has been shown to stabilize p53 during oxidative stress, promoting its translocation to the mitochondria and encouraging mitochondrial- related necrosis.[17] In addition, cyclin B1- CDK activates Drp1, causing fragmentation and ensuring mitochondria are distributed to each daughter cell after mitosis. Likewise, different transcriptional controllers are able to alter Drp1 activity through gene expression and regulation. For example, PPARGC1A and [HIF1A] regulated Drp1 activity through gene expression.[9]
Therapy
Inhibition of Drp1 has been considered for possible therapeutics for a variety of diseases. The most studied inhibitor is a small molecule named mitochondrial division inhibitor 1 (mdivi¬1) which in fact inhibits complex 1 on the mitochondrial respiratory chain.[18] The inhibitors putative function is preventing the GTPase activity of Drp1. Preventing the activation and localization to the mitochondria.[9] Midiv-1 has been demonstrated to attenuate the effects of ischemia reperfusion injury after cardiac arrest. The treatment prevented both mitochondria fragmentation and increased cell viability.[19] Similarly, midiv-1 has demonstrated neuroprotective effects by greatly reducing neuron death due to seizure. Furthermore, the study showed midiv-1 was capable to preventing the activation of caspase 3 by reversing the release of cytochrome c in intrinsic apoptosis.[20] Whether mdivi-1 inhibits Drp1 or not, it's therapeutic potential is certainly evident. Other than directly inhibiting Drp1, certain inhibitors of proteins involved in the posttranslational modifications of Drp1 have been studied. FK506 is a calcineurin inhibitor, which functions to dephosphorylate the serine 637 position of Drp1, encouraging translocation to the mitochondria and fragmentation. FK506 was shown to also preserve mitochondrial morphology after reperfusion injury.[19]
References
↑Shin HW, Shinotsuka C, Torii S, Murakami K, Nakayama K (Sep 1997). "Identification and subcellular localization of a novel mammalian dynamin-related protein homologous to yeast Vps1p and Dnm1p". Journal of Biochemistry. 122 (3): 525–30. doi:10.1093/oxfordjournals.jbchem.a021784. PMID9348079.
↑ 2.02.1Hong YR, Chen CH, Cheng DS, Howng SL, Chow CC (Aug 1998). "Human dynamin-like protein interacts with the glycogen synthase kinase 3beta". Biochemical and Biophysical Research Communications. 249 (3): 697–703. doi:10.1006/bbrc.1998.9253. PMID9731200.
↑ 4.04.14.2Westermann B (Dec 2010). "Mitochondrial fusion and fission in cell life and death". Nature Reviews Molecular Cell Biology. 11 (12): 872–84. doi:10.1038/nrm3013. PMID21102612.
↑ 9.09.19.2Archer SL (Dec 2013). "Mitochondrial dynamics--mitochondrial fission and fusion in human diseases". The New England Journal of Medicine. 369 (23): 2236–51. doi:10.1056/NEJMra1215233. PMID24304053.
↑Zhang C, Yuan XR, Li HY, Zhao ZJ, Liao YW, Wang XY, Su J, Sang SS, Liu Q (Jan 2014). "Downregualtion of dynamin-related protein 1 attenuates glutamate-induced excitotoxicity via regulating mitochondrial function in a calcium dependent manner in HT22 cells". Biochemical and Biophysical Research Communications. 443 (1): 138–43. doi:10.1016/j.bbrc.2013.11.072. PMID24284040.
↑Lackner LL, Horner JS, Nunnari J (Aug 2009). "Mechanistic analysis of a dynamin effector". Science. 325 (5942): 874–7. doi:10.1126/science.1176921. PMID19679814.
↑Xie N, Wang C, Lian Y, Zhang H, Wu C, Zhang Q (Jun 2013). "A selective inhibitor of Drp1, mdivi-1, protects against cell death of hippocampal neurons in pilocarpine-induced seizures in rats". Neuroscience Letters. 545: 64–8. doi:10.1016/j.neulet.2013.04.026. PMID23628672.
Further reading
Pawlikowska P, Orzechowski A (2007). "[Role of transmembrane GTPases in mitochondrial morphology and activity]". Postepy Biochemii. 53 (1): 53–9. PMID17718388.
Kamimoto T, Nagai Y, Onogi H, Muro Y, Wakabayashi T, Hagiwara M (Jan 1998). "Dymple, a novel dynamin-like high molecular weight GTPase lacking a proline-rich carboxyl-terminal domain in mammalian cells". The Journal of Biological Chemistry. 273 (2): 1044–51. doi:10.1074/jbc.273.2.1044. PMID9422767.
Imoto M, Tachibana I, Urrutia R (May 1998). "Identification and functional characterization of a novel human protein highly related to the yeast dynamin-like GTPase Vps1p". Journal of Cell Science. 111 (10): 1341–9. PMID9570752.
Koch A, Thiemann M, Grabenbauer M, Yoon Y, McNiven MA, Schrader M (Mar 2003). "Dynamin-like protein 1 is involved in peroxisomal fission". The Journal of Biological Chemistry. 278 (10): 8597–605. doi:10.1074/jbc.M211761200. PMID12499366.
Li X, Gould SJ (May 2003). "The dynamin-like GTPase DLP1 is essential for peroxisome division and is recruited to peroxisomes in part by PEX11". The Journal of Biological Chemistry. 278 (19): 17012–20. doi:10.1074/jbc.M212031200. PMID12618434.
Howng SL, Sy WD, Cheng TS, Lieu AS, Wang C, Tzou WS, Cho CL, Hong YR (Feb 2004). "Genomic organization, alternative splicing, and promoter analysis of human dynamin-like protein gene". Biochemical and Biophysical Research Communications. 314 (3): 766–72. doi:10.1016/j.bbrc.2003.12.172. PMID14741701.
Pitts KR, McNiven MA, Yoon Y (Nov 2004). "Mitochondria-specific function of the dynamin family protein DLP1 is mediated by its C-terminal domains". The Journal of Biological Chemistry. 279 (48): 50286–94. doi:10.1074/jbc.M405531200. PMID15364948.
Goehler H, Lalowski M, Stelzl U, Waelter S, Stroedicke M, Worm U, Droege A, Lindenberg KS, Knoblich M, Haenig C, Herbst M, Suopanki J, Scherzinger E, Abraham C, Bauer B, Hasenbank R, Fritzsche A, Ludewig AH, Büssow K, Buessow K, Coleman SH, Gutekunst CA, Landwehrmeyer BG, Lehrach H, Wanker EE (Sep 2004). "A protein interaction network links GIT1, an enhancer of huntingtin aggregation, to Huntington's disease". Molecular Cell. 15 (6): 853–65. doi:10.1016/j.molcel.2004.09.016. PMID15383276.